Uncovering the true burden of hereditary angioedema due to C1-inhibitor deficiency: A focus on the Asia-Pacific region
Authors: Daisuke Honda, Philip Hei Li, Ankur Kumar Jindal, Constance H. Katelaris, Yu-Xiang Zhi, Bernard Yu-Hor Thong, Hilary J. Longhurst
Journal: Journal of Allergy and Clinical Immunology (2023)

Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments. Hereditary angioedema (HAE) due to C1-inhibitor deficiency or dysfunction is a rare genetic disorder that causes recurrent episodes of swelling in various parts of the body. Treatment goals of HAE aim to "normalize" life for all patients; however, lack of diagnostic facilities and limited access to effective treatment options in developing nations cause delays in diagnosis and place a significant burden on patients. In this review, we aim to highlight the burden of disease caused by C1-inhibitor HAE across the Asia-Pacific region, considering its epidemiology, morbidity and mortality, and socioeconomic and psychological impact. We also review the availability of guideline-recommended diagnostic facilities and treatments, and how patients are currently managed. Data were collected from published literature and HAE experts in the region, who provided information regarding diagnosis and management in their countries. Current practice was reviewed against international guidelines, as well as local guidelines/consensus used in Australia, Japan, and China. Suggestions are provided for improving the time to diagnosis in the region, increasing access to guideline-recommended treatments, and providing support to reduce the burden on patients and caregivers. There is an urgent need to improve HAE services and provide access to life-saving treatment in developing countries, and efforts should be made to increase awareness of guideline recommendations in high-income economies that do not currently provide long-term prophylactic treatments. Hereditary angioedema (HAE) due to C1-esterase inhibitor deficiency or dysfunction (C1-INH-HAE) is a rare, potentially life-threatening disease characterized by recurrent acute attacks of skin and/or mucosal edema.1Maurer M. Magerl M. Betschel S. Aberer W. Ansotegui I.J. Aygören-Pürsün E. et al.The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update.Allergy. 2022; 77: 1961-1990Crossref PubMed Scopus (120) Google Scholar,2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar The disease is primarily driven by deficiency or dysfunction in C1-INH protein (HAE types 1 and 2, respectively), which leads to dysregulation of the kallikrein-kinin pathway and overproduction of bradykinin, a potent mediator of the inflammatory cascade responsible for vasodilation and vascular permeability.1Maurer M. Magerl M. Betschel S. Aberer W. Ansotegui I.J. Aygören-Pürsün E. et al.The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update.Allergy. 2022; 77: 1961-1990Crossref PubMed Scopus (120) Google Scholar,2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar C1-INH-HAE is a chronic disorder with high morbidity and negative impact on patient quality of life (QoL) because of repeated attacks of angioedema, which may be fatal when localized to the larynx.3Banerji A. Davis K.H. Brown T.M. Hollis K. Hunter S.M. Long J. et al.Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States.Ann Allergy Asthma Immunol. 2020; 124: 600-607Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Without access to effective acute and prophylactic treatments, mortality caused by laryngeal edema is high.4Agostoni A. Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.Medicine (Baltimore). 1992; 71: 206-215Crossref PubMed Scopus (575) Google Scholar Historical mortality rates before effective treatments in Western populations were approximately 30%,4Agostoni A. Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.Medicine (Baltimore). 1992; 71: 206-215Crossref PubMed Scopus (575) Google Scholar which reflects current trends in developing Asian nations. Median age of those who died from C1-INH-HAE in a recent Chinese survey was 46 years (interquartile range: 35-53 years).5Cao Y. Liu S. Zhi Y. The natural course of hereditary angioedema in a Chinese cohort.Orphanet J Rare Dis. 2020; 15: 257Crossref PubMed Scopus (5) Google Scholar However, because access to guideline-recommended treatments has increased, mortality in C1-INH-HAE has been lowered significantly, although, at the present time, this reduction is limited to high-income countries.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,6Bork K. Hardt J. Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency.J Allergy Clin Immunol. 2012; 130: 692-697Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar In developing countries across the Asia-Pacific (APAC) region, early recognition and timely intervention with guideline-recommended treatment are crucial areas of unmet need.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar In particular, because of the cost of disease-specific treatment such as plasma-derived C1-INH (pdC1-INH) or recombinant C1-INH, lanadelumab, berotralstat, ecallantide, and icatibant, many developing countries have little to no access to guideline-recommended options.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,5Cao Y. Liu S. Zhi Y. The natural course of hereditary angioedema in a Chinese cohort.Orphanet J Rare Dis. 2020; 15: 257Crossref PubMed Scopus (5) Google Scholar,7Hanizah N. Affirul C.A. Farah N.A. Shamila M.A. Ridzuan M.I. Novel usage of fresh frozen plasma in hereditary angioedema.Clin Ter. 2016; 167: 182-184PubMed Google Scholar This review aims to highlight the true burden of disease caused by C1-INH-HAE across the APAC region, considering its epidemiology, morbidity and mortality, socioeconomic and psychological impact, and availability of guideline-recommended treatments. The authors will uncover areas that require significant attention from governments and health authorities and outline potential action points that can have the greatest positive impact on patients. Worldwide, the prevalence of HAE is thought to be approximately 1:50,000, although this estimate ranges between 1:10,000 and 1:150,000.1Maurer M. Magerl M. Betschel S. Aberer W. Ansotegui I.J. Aygören-Pürsün E. et al.The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update.Allergy. 2022; 77: 1961-1990Crossref PubMed Scopus (120) Google Scholar In developing nations across the APAC region, a recent survey estimated a median overall prevalence of 0.02 per 100,000; however, a large range was observed between countries, with some estimates as high as 0.33 to1.00 per 100,000 (in Singapore and New Zealand) and as low as 0.02 per 100,000 (India).8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Given the large population in this area of the world (roughly 46% of the global population),8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar it is likely that there are a significant number of people living with undiagnosed HAE (Fig 1).2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 9World population total. World Bank Data.https://data.worldbank.org/indicator/SP.POP.TOTLDate accessed: September 1, 2023Google Scholar, 10Lindsay K. Chua I. Jordan A. Stephens S. National audit of a hereditary and acquired angioedema cohort in New Zealand.Intern Med J. 2022; 52: 2124-2129Crossref PubMed Scopus (1) Google Scholar, 11Lei W.T. Shyur S.D. Huang L.H. Kao Y.H. Lo C.Y. Type I hereditary angioedema in Taiwan -- clinical, biological features and genetic study.Asian Pac J Allergy Immunol. 2011; 29: 327-331PubMed Google Scholar, 12Cui Q. Xu Q. Yang Y. Li W. Huang N. Chen H. et al.The prevalence of hereditary angioedema in a Chinese cohort with decreased complement 4 levels.World Allergy Organ J. 2021; 15100620PubMed Google Scholar Vast heterogeneity has also been noted among regions with similar ethnic backgrounds, for example, in Han Chinese-predominant regions such as Hong Kong (China) and Mainland China, with an estimated prevalence of 0.60 and 0.04 per 100,000 population, respectively.8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Even in developed Asian nations, such as Japan, HAE is not well documented, with estimates for prevalence ranging significantly, from 0.02 per 100,000 to as many as 1 in 10,000, with exact patient numbers unknown.8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,13Hirose T. Kimbara F. Shinozaki M. Mizushima Y. Yamamoto H. Kishi M. et al.Screening for hereditary angioedema (HAE) at 13 emergency centers in Osaka, Japan: a prospective observational study.Medicine (Baltimore). 2017; 96e6109Crossref PubMed Scopus (8) Google Scholar In Hong Kong, following implementation of a systematic family screening program, the estimated point prevalence of C1-INH-HAE increased from 0.16 to 0.60 per 100,000 within a span of 2 years.14Wong J.C.Y. Chiang V. Lam K. Tung E. Au E.Y.L. Lau C.S. et al.Prospective study on the efficacy and impact of cascade screening and evaluation of hereditary angioedema (CaSE-HAE).J Allergy Clin Immunol Pract. 2022; 10: 2896-2903.e2Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar This demonstrates the potential of improving diagnostic capacity and family screening in the APAC region.14Wong J.C.Y. Chiang V. Lam K. Tung E. Au E.Y.L. Lau C.S. et al.Prospective study on the efficacy and impact of cascade screening and evaluation of hereditary angioedema (CaSE-HAE).J Allergy Clin Immunol Pract. 2022; 10: 2896-2903.e2Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The APAC region is densely populated and is likely home to the largest number of undiagnosed patients with HAE in the world.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,9World population total. World Bank Data.https://data.worldbank.org/indicator/SP.POP.TOTLDate accessed: September 1, 2023Google Scholar These data suggest that many patients across the region are living with undiagnosed C1-INH-HAE, especially in low-income countries: up to 99% of patients remain undiagnosed in India versus roughly 50% in Australia and New Zealand.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,10Lindsay K. Chua I. Jordan A. Stephens S. National audit of a hereditary and acquired angioedema cohort in New Zealand.Intern Med J. 2022; 52: 2124-2129Crossref PubMed Scopus (1) Google Scholar Because of the relative availability and accessibility of modern diagnostic methods and treatments in Western nations, mortality due to HAE has been significantly reduced.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,15Bork K. Siedlecki K. Bosch S. Schopf R.E. Kreuz W. Asphyxiation by laryngeal edema in patients with hereditary angioedema.Mayo Clin Proc. 2000; 75: 349-354Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar However, morbidity and mortality in undiagnosed patients have been found to be much higher than in diagnosed patients.1Maurer M. Magerl M. Betschel S. Aberer W. Ansotegui I.J. Aygören-Pürsün E. et al.The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update.Allergy. 2022; 77: 1961-1990Crossref PubMed Scopus (120) Google Scholar,2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,15Bork K. Siedlecki K. Bosch S. Schopf R.E. Kreuz W. Asphyxiation by laryngeal edema in patients with hereditary angioedema.Mayo Clin Proc. 2000; 75: 349-354Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar Delay in diagnosis is a problem, even in developed nations. Although the median delay in diagnosis has improved recently to 2.6 years for C1-INH-HAE (reduced from 12.8 years a decade ago),5Cao Y. Liu S. Zhi Y. The natural course of hereditary angioedema in a Chinese cohort.Orphanet J Rare Dis. 2020; 15: 257Crossref PubMed Scopus (5) Google Scholar,16Zanichelli A. Magerl M. Longhurst H. Fabien V. Maurer M. Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe.Allergy Asthma Clin Immunol. 2013; 9: 29Crossref PubMed Scopus (110) Google Scholar the variation in delay in diagnosis is still very large, ranging from 0.13 years to 17.3 years.17Zanichelli A. Magerl M. Longhurst H.J. Aberer W. Caballero T. Bouillet L. et al.Improvement in diagnostic delays over time in patients with hereditary angioedema: findings from the Icatibant Outcome Survey.Clin Transl Allergy. 2018; 8: 42Crossref PubMed Scopus (28) Google Scholar Even in situations in which a patient had a family member with C1-INH-HAE, the time to diagnosis may not be reduced versus that for those with a negative history, suggesting that patients may not be aware of the hereditary nature of the disease or may fail to come forward for diagnosis for other reasons, such as previous lack of benefit from medical services.16Zanichelli A. Magerl M. Longhurst H. Fabien V. Maurer M. Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe.Allergy Asthma Clin Immunol. 2013; 9: 29Crossref PubMed Scopus (110) Google Scholar This delay in diagnosis puts patients at greatly increased risk of premature death from asphyxiation, as well as exposes them to the social and economic consequences of untreated C1-INH-HAE.16Zanichelli A. Magerl M. Longhurst H. Fabien V. Maurer M. Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe.Allergy Asthma Clin Immunol. 2013; 9: 29Crossref PubMed Scopus (110) Google Scholar Unpublished observations from India suggest that delay in diagnosis is the most important factor leading to mortality in patients with C1-INH-HAE. Undiagnosed HAE or an "uncertain diagnosis" of HAE also leads to elevated anxiety in both symptomatic patients and asymptomatic family members, which can be alleviated after allergist/immunologist assessment and advice.14Wong J.C.Y. Chiang V. Lam K. Tung E. Au E.Y.L. Lau C.S. et al.Prospective study on the efficacy and impact of cascade screening and evaluation of hereditary angioedema (CaSE-HAE).J Allergy Clin Immunol Pract. 2022; 10: 2896-2903.e2Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The delay in diagnosis varies widely in Asian nations, with patients being diagnosed as young as at birth and as old as at 72 years,8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar if indeed they are diagnosed at all. In India, for example, although 1 study reported a mean delay in diagnosis of 6.5 years (range, 0-28 years),2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar the authors acknowledged that this estimate is likely inaccurate given that there are only 130 confirmed cases in a country of approximately 1.38 billion people, and that it is typical for older generations to receive their diagnosis only after their grandchildren have been diagnosed.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar In South Korea, it took 7.75 ± 10.54 years for a definitive diagnosis.18Iwamoto K. Yamamoto B. Ohsawa I. Honda D. Horiuchi T. Tanaka A. et al.The diagnosis and treatment of hereditary angioedema patients in Japan: a patient reported outcome survey.Allergol Int. 2021; 70: 235-243Crossref PubMed Scopus (15) Google Scholar,19Jung J.W. Suh D.I. Park H.J. Kim S. Kwon H.S. Yang M.S. et al.Clinical features of hereditary angioedema in Korean patients: a nationwide multicenter study.Int Arch Allergy Immunol. 2018; 176: 272-279Crossref PubMed Scopus (20) Google Scholar One study in China reported a mean delay in diagnosis of 11.04 to 12.64 years, and in Japan (arguably the most developed Asian nation as far as HAE is concerned),5Cao Y. Liu S. Zhi Y. The natural course of hereditary angioedema in a Chinese cohort.Orphanet J Rare Dis. 2020; 15: 257Crossref PubMed Scopus (5) Google Scholar,20Liu S. Wang X. Xu Y. Xu Q. Zhi Y. Risk factors for diagnostic delay in Chinese patients with hereditary angioedema.Allergy Asthma Proc. 2019; 40: 343-349Crossref PubMed Scopus (14) Google Scholar the delay was particularly long, at 15.6 ± 13.3 years.18Iwamoto K. Yamamoto B. Ohsawa I. Honda D. Horiuchi T. Tanaka A. et al.The diagnosis and treatment of hereditary angioedema patients in Japan: a patient reported outcome survey.Allergol Int. 2021; 70: 235-243Crossref PubMed Scopus (15) Google Scholar Interestingly, in China, it was found that the decade in which patients started to experience symptoms, there was a significant impact on the diagnostic delay (P < .001), with those who had symptom onset before 1999 experiencing a delay of 19.75 years, between 2000 and 2009 a delay of 8.67 years, and between 2010 and 2017 a delay of 3.79 years.20Liu S. Wang X. Xu Y. Xu Q. Zhi Y. Risk factors for diagnostic delay in Chinese patients with hereditary angioedema.Allergy Asthma Proc. 2019; 40: 343-349Crossref PubMed Scopus (14) Google Scholar Awareness of HAE among physicians and the public is notably low,2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar with a survey conducted in Japan including more than 9000 physicians documenting that only 44.8% had any degree of awareness regarding HAE.21Ohsawa I. Hereditary angioedema recognition survey in Japan [in Japanese].Pharma Med. 2011; 29: 109e18Google Scholar In terms of trained allergists/immunologists, several Asian nations have inadequate numbers of these essential clinicians.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar Specifically, India has a single training program in pediatric immunology, with only 11 physicians completing their training as of 2021.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar Hong Kong initiated its inaugural training center for immunology and allergy in 2021 and currently has just 2 practicing specialists in this domain. Singapore does not maintain a dedicated specialty for immunology and allergy; instead, it relies on rheumatology specialists to cultivate subspecialty interests in this area. Testing for C1-INH function in the laboratory is not generally available in developing Asian nations, which could account for the lack of diagnosed patients.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar Diagnostic facilities for HAE, including genetic testing, are limited and mostly available only at large tertiary centers or university hospitals, even in more developed nations.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Testing complement component 4 (C4) levels is the most widely available test in the region, but pitfalls include suboptimal sensitivity and specificity.8Li P.H. Pawankar R. Thong B.Y. Fok J.S. Chantaphakul H. Hide M. et al.Epidemiology, management, and treatment access of hereditary angioedema in the Asia Pacific region: outcomes from an international survey.J Allergy Clin Immunol Pract. 2023; 11: 1253-1260Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Where testing for C1-INH levels is available, tests are challenging to conduct because of a lack of local technical expertise and the need for careful sample handling.2Jindal A.K. Reshef A. Longhurst H. Global Equity in HAE Management WorkgroupMitigating disparity in health-care resources between countries for management of hereditary angioedema.Clin Rev Allergy Immunol. 2021; 61: 84-97Crossref PubMed Scopus (17) Google Scholar,13Hirose T. Kimbara F. Shinozaki M. Mizushima Y. Yamamoto H. Kishi M. et al.Screening for hereditary angioedema (HAE) at 13 emergency centers in Osaka, Japan: a prospective observational study.Medicine (Baltimore). 2017; 96e6109Crossref PubMed Scopus (8) Google Scholar In Japan, for example, evaluation of the antigenic level of C1-INH is not covered by the national health insurance system, and so diagnosis of C1-INH-HAE is obtained on the basis of clinical history and measurement of C4 and (preferably) C1-INH function, which is usually available only in reference centers and may be subject to sample-handling error. Availability of genetic testing for HAE is variable; for example, only 20% of Japanese patients with suspected HAE receive genetic testing, which can be useful in instances wherein standard test results are inconclusive, prenatal or early postnatal diagnosis is required, or wherein sample transport issues preclude the use of standard tests.18Iwamoto K. Yamamoto B. Ohsawa I. Honda D. Horiuchi T. Tanaka A. et al.The diagnosis and treatment of hereditary angioedema patients in Japan: a patient reported outcome survey.Allergol Int. 2021; 70: 235-243Crossref PubMed Scopus (15) Google Scholar In China, the evaluation of antigenic levels of C4 and C1-INH is covered by the National Health Insurance System. Although C4 is widely tested in most hospitals, antigenic testing of C1-INH levels is available in fewer than 10 centers. Testing for functional C1-INH has not been approved and is used only in research when a patient is suspected to have HAE type 2. In HAE, acute attacks of angioedema can be localized anywhere on the body; however, the most common sites are the extremities (Fig 2),22Agostoni A. Aygören-Pürsün E. Binkley K.E. Blanch A. Bork K. Bouillet L. et al.Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.J Allergy Clin Immunol. 2004; 114: S51-S131Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar gastrointestinal tract (Fig 3),23Honda D. Ohsawa I. Iwanami K. Rinno H. Tomino Y. Suzuki Y. A case of hereditary angioedema due to C1-inhibitor deficiency with recurrent abdominal pain diagnosed 40 years after the occurrence of the initial symptom.Clin J Gastroenterol. 2021; 14: 1175-1179Crossref PubMed Scopus (1) Google Scholar face and larynx (Fig 4), and genitals. Single-site attacks occur most frequently, but migratory, simultaneous, or closely spaced attacks can also occur.22Agostoni A. Aygören-Pürsün E. Binkley K.E. Blanch A. Bork K. Bouillet L. et al.Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.J Allergy Clin Immunol. 2004; 114: S51-S131Abstract Full Text Full Text PDF PubMed Scopus (591) Google ScholarFig 3A and B, Abdominal computed tomography scan in a patient with HAE during an acute attack: axial section (A) and coronal section (B). Submucosal edema of the intestinal tracts is observed during an acute attack (white arrows). Colectasia is observed (B), which was probably caused by the attenuation of peristalsis due to 11 previous surgical procedures (black arrows). Images reproduced with permission from Honda et al.23Honda D. Ohsawa I. Iwanami K. Rinno H. Tomino Y. Suzuki Y. A case of hereditary angioedema due to C1-inhi